INHIBITORS OF STEROL SYNTHESIS - ,26,27,27,27-HEPTAFLUORO-5-ALPHA-CHOLESTAN-15-ONE, AN ANALOG OF A POTENT HYPOCHOLESTEROLEMIC AGENT IN WHICH ITS MAJOR METABOLISM IS BLOCKED

The chemical synthesis of 3 beta-hydroxy-25,26,26,26,27,27,27-heptaflu oro-5 alpha-cholestan-15-one (IV) has been pursued to provide an analo g of the potent hypocholesterolemic agent 3 beta-hydroxy-5 alpha-chole st-8(14)-en-15-one (I) in which its major metabolism is blocked. Reduc tion of 3 beta-acetoxy-5 alpha-chola-8(14),23-dien-15-one with lithium in liquid ammonia gave 3 beta-hydroxy-5 alpha-chol-23-en-15-one (VI). Addition of (CF3)(2)CFI to VI in the presence of triethyl borane gave 3 ydroxy-23R-iodo-25,26,26,26,27,27,27-heptafluoro-5 alpha-choldestan -15-one, which was reduced to IV with tributyltin hydride. IV was foun d to be highly active in lowering the levels of HMG-CoA reductase acti vity in CHO-K1 cells, in lowering acyl coenzyme A:cholesterol acyltran sferase activity in jejunal microsomes, and in lowering serum choleste rol levels in rats. (C) 1994 Academic Press, Inc.